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The inhibition of protein translation promotes tumor angiogenic switch

Hui Luo1, Yuge Shen1, Weiting Liao1

  • 1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No.17 Renmin South Road Section Three, Chengdu, 610041, Sichuan, China.

Molecular Biomedicine
|June 13, 2022
PubMed

Insights

Tumor growth relies on the angiogenic switch, but its mechanisms are unclear. This study reveals that inhibiting translation, not hypoxia, drives this switch by boosting vascular endothelial growth factor A (Vegfa) expression in zebrafish models.

Area of Science:

  • Oncology
  • Developmental Biology
  • Molecular Biology

Background:

  • The 'angiogenic switch' is a critical, yet incompletely understood, process in tumor progression.
  • Tumor neovascularization is essential for growth and metastasis, but the precise molecular triggers remain elusive.

Purpose of the Study:

  • To investigate the molecular mechanisms and pathological details of the angiogenic switch in real-time.
  • To determine the roles of hypoxia, hypoxia-inducible factor (HIF) signaling, and vascular endothelial growth factor A (Vegfa) in initiating tumor angiogenesis.

Main Methods:

  • Establishment of mammal xenografts in transparent zebrafish larvae (flk1:EGFP) for in vivo visualization.
  • Transcriptome analysis to identify molecular changes during the angiogenic switch.
  • Manipulation of Vegfa expression and translation inhibition (puromycin treatment) in tumor cells and xenografts.

Main Results:

  • Hypoxia and HIF signaling were found to be unnecessary for the angiogenic switch.
  • Inhibition of translation, specifically via eukaryotic translation initiation factor 2 alpha (Eif2α) phosphorylation, was identified as a key event.
  • Vascular endothelial growth factor A (Vegfa) played a crucial role; its overexpression accelerated the switch, while its knockout prevented vessel sprouting.
  • Puromycin treatment mimicked Vegfa overexpression effects, promoting the angiogenic switch.

Conclusions:

  • The angiogenic switch is promoted by the inhibition of translation, leading to increased Vegfa transcription, rather than by hypoxia or HIF signaling.
  • This study provides direct in vivo evidence for translation inhibition as a driver of tumor angiogenesis.
Keywords:
Angiogenic switchHIFMicrotumorProtein translationVegfa

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